Plasma concentrations of progesterone are higher in the uterine artery than in the radial artery after vaginal administration of micronized progesterone in an oil-based solution to postmenopausal women
Ettore Cicinelli, F Romano, L M Schonauer
N. Einer‐Jensen , M Cignarelli , N Einer-Jensen , R Padovano , S Sabatelli
Author affiliations
Unit of Obstetrics and Gynecology, Department of Biomedical and Human Oncologic Science, University of Bari, 70124 Bari, ItalyROR
To verify the occurrence of preferential distribution of vaginally administered progesterone to the uterus compared with extrapelvic regions in vivo and in humans.
Design
Prospective clinical study.
Setting
University medical school.
PATIENT(S): Twenty postmenopausal women undergoing transabdominal hysterectomy for benign pathologies.
INTERVENTION(S): Forty-five minutes before surgery, the women received a single vaginal administration of an oil-based micronized progesterone (100 mg) solution currently available on the market for IM use. During the operation, parallel blood samples were drawn from the uterine and radial arteries.
MAIN OUTCOME MEASURE(S): Plasma levels of progesterone were measured by RIA.
RESULT(S): Mean (+/- SD) plasma levels of progesterone were significantly higher in the uterine artery than in the radial artery (9.75 +/- 3.21 vs. 5.12 +/- 2.06 ng/mL, respectively).
CONCLUSION(S): Vaginal administration allows a preferential distribution of progesterone to the uterus, which confirms the existence of the so-called "first uterine pass effect."
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PMID 9531879 9531879 DOI 10.1016/s0015-0282(97)00545-1 10.1016/s0015-0282(97)00545-1
Cite this article
Cicinelli, E., Cignarelli, M., Sabatelli, S., Romano, F., Schonauer, L. M., Padovano, R., & Einer-Jensen, N. (1998). Plasma concentrations of progesterone are higher in the uterine artery than in the radial artery after vaginal administration of micronized progesterone in an oil-based solution to postmenopausal women. Fertility and sterility, 69(3), 471-473. https://doi.org/10.1016/s0015-0282(97)00545-1
Cicinelli E, Cignarelli M, Sabatelli S, Romano F, Schonauer LM, Padovano R, et al. Plasma concentrations of progesterone are higher in the uterine artery than in the radial artery after vaginal administration of micronized progesterone in an oil-based solution to postmenopausal women. Fertil Steril. 1998;69(3):471-473. doi:10.1016/s0015-0282(97)00545-1
Cicinelli, E., et al. "Plasma concentrations of progesterone are higher in the uterine artery than in the radial artery after vaginal administration of micronized progesterone in an oil-based solution to postmenopausal women." Fertility and sterility, vol. 69, no. 3, 1998, pp. 471-473.
To determine pharmacokinetic and endometrial effects of vaginally delivered micronized P. Functionally agonadal estrogen-replacement recipients received either micronized P administered vaginally or bi-daily IM injections of P. Hourly blood samples were obtained, from baseline to 6 hours after the initial dose of P and again on simulated cycle day 21 when transvaginal ultrasound (US) measurements and tissue samples of the endometrium were performed. Blood and tissue samples were assayed for P. Endometrial histology, estrogen receptor (ER) and P receptor (PR) contents were evaluated. University of Southern California School of Medicine, Los Angeles, California. Twenty functionally agonadal and four normally ovulating women. Delivery differences were assessed by [1] endometrial P concentrations; [2] USs; [3] histologic datings; [4] ER and PR contents, and [5] serum P levels. Endometrial P concentrations were higher with vaginally administered P than endometrial concentrations observed in normal ovulatory women or women who consistently had the highest serum P after IM administration (11.50 +/- 2.60 versus 1.40 +/- 0.40 versus 0.30 +/- 0.10 ng/mg protein [36.56 +/- 8.27 versus 4.45 +/- 1.27 versus 0.95 +/- 0.32 nmol/L], respectively). After 7 days of P, no differences between either treatment regimen and control groups were detected by histologic, ultrasonographic, or immunocytochemical receptor analyses. Vaginal micronized P enhances P delivery to the uterus compared with a standard IM regimen and results in a synchronous secretory endometrial histology in agonadal women preparing for embryo donation.
Reproductive EndocrinologyVaginal Administration PharmacokineticsFirst Uterine Pass EffectTargeted Uterine Drug Delivery
The objective was to verify the hypothesis of a 'first uterine pass effect' or direct preferential vagina-to-uterus transport, suggested by the evidence of higher than expected uterine tissue concentrations after vaginal administration of progesterone; we used a human ex-vivo uterine perfusion model. A mixture of tritiated (3H) and unlabelled progesterone was applied to the cuff of vaginal tissue remaining attached to the cervix after hysterectomy. At the end of the perfusion period (up to 12 h), 3H and 14C radioactivity was measured in samples of uterine tissue. Tritiated water and [14C]dextran were tested to determine the extent of non-specific vagina-to-uterus transport (leaks). Finally, sections of uterine tissue exposed only to [3H]progesterone were prepared for autoradiography. By 4-5 h after application progesterone had diffused to the entire uterus and had reached a steady state; 4 h after application, progesterone concentrations reached 185 +/- 155 and 254 +/- 305 ng/100 mg of endometrial and myometrial tissue respectively. Endometrial extraction of progesterone was higher when the experiment was performed on uteri obtained during the luteal phase (280 +/- 156 ng/100 mg of endometrial tissue) than those removed during the proliferative phase of the menstrual cycle (74 +/- 28 ng/100 mg of endometrial tissue). These data demonstrate that a 'first uterine pass effect' occurs when drugs are delivered vaginally, thereby providing an explanation for the unexpectedly high uterine concentrations relative to the low serum concentration observed after vaginal administration. Hence, the vaginal route permits targeted drug delivery to the uterus, thereby maximizing the desired effects while minimizing the potential for adverse systemic effects.
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